Heterozygous Variants in Idiopathic Short Stature.

Heterozygous variants in the gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2-6% cases of idiopathic short stature (ISS). Using next-generation sequencing (NGS), we aimed to assess the frequency of variants in our study cohort consisting of 150 children and adolescents with ISS, describe the phenotypic spectrum with a growth pattern including birth data, and study the response to growth hormone (GH) treatment. A total of ten heterozygous pathogenic/likely pathogenic variants and two heterozygous variants of uncertain significance were detected in twelve participants (frequency of causal variants: 10/150, 6.7%). During follow-up, the individuals presented with a growth pattern varying from low-normal to significant short stature. A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in individuals, was observed. In total, 8.8% participants born small for their gestational age (SGA) carried the causal variant. The response to GH treatment was variable (SDS height gain ranging from -0.01 to +0.74). According to the results, variants present a frequent cause of ISS and familial short stature. Phenotyping variability in growth patterns and variable responses to GH treatment should be considered.